Cosmetic and pharmaceutical foam

ABSTRACT

The invention relates to an alcohol-free cosmetic or pharmaceutical foam carrier comprising water, a hydrophobic solvent, a foam adjuvant agent, a surface-active agent and a water gelling agent. The cosmetic or pharmaceutical foam carrier does not contain aliphatic alcohols, making it non-irritating and non-drying. The alcohol-free foam carrier is suitable for inclusion of both water-soluble and oil soluble pharmaceutical and cosmetic agents.

This application claims priority to Related Applications of Israelipatent application No. 152486 filed Oct. 25, 2002 entitled “Alcohol-freeCosmetic and Pharmaceutical Foam Carrier”, and to U.S. provisionalpatent application No. 60/495,546, filed Nov. 29, 2002, entitled“Cosmetic and Pharmaceutical Foam”, which are incorporated herein intheir entirety.

FIELD OF THE INVENTION

The invention relates to an alcohol-free, cosmetic or pharmaceuticalfoam carrier and its use. More specifically, the invention relates to acosmetic or pharmaceutical foam carrier suitable for inclusion of bothwater soluble and oil soluble pharmaceutical and cosmetic agents.

BACKGROUND OF THE INVENTION

External topical administration is an important route for theadministration of drugs in disease treatment. In external topicaladministration, the drug is absorbed into and/or through skin, mucousmembrane or wound tissue. Many groups of drugs, including, for example,antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic,anti-allergic, corticosteroid, retinoid and anti-proliferativemedications are preferably administered in hydrophobic media, e.g.ointments or oils. However, due to the undesirable consistency of thesehydrophobic carriers, their use is limited. For instance, ointmentscontaining white petrolatum, e.g., Vaseline petroleum jelly, as thecarrier often form an impermeable barrier, so that metabolic productsand excreta from the wounds to which they are applied are not easilyremoved or drained away. Furthermore, it is difficult for the activedrug dissolved in the carrier to pass through the white petrolatumbarrier layer into the wound tissue, so the efficacy of the drug isreduced.

In addition, ointments and creams often do not create an environment forpromoting respiration of the wound tissue and it is not favorable to thenormal respiration of the skin. An additional disadvantage of petroleumjelly-based products relates to the greasy feeling left following theirtopical application onto the skin, mucosal membranes and wounds. Besidespetroleum jelly, hydrophobic pharmaceutical carriers now in use includeliquid paraffin, lanolin, beeswax, vegetable oil, glycerin monostearate,higher alcohols, polyethylene glycol and some emulsifying agents, whichalso have undesirable flow properties and skin feel.

Several hydrophobic liquid and semi-solid oils, e.g., mono- andpoly-unsaturated oils from vegetable and marine sources, mineral oils,silicone oils, and liquid hydrophobic plant-derived oils, are known fortheir therapeutic benefits when applied topically, yet, theirapplication in liquid form is not practical. Oils can also containessential nutritional constituents, such as oil-soluble vitamins (e.g.,vitamin A and vitamin E), minerals and other therapeutically beneficialconstituents. Another class of therapeutic oils includes mineral andsilicon oils useful for the treatment of skin dehydration and othermedical disorders, which oils are liquid at ambient temperature. Suchtherapeutic oils unfortunately, cannot be applied by users in amountssufficient to exert therapeutic affects because of they typically areliquid at use temperatures.

Other pharmaceutical active ingredients are water-soluble and require awater component in the carrier.

While semi-solid cosmetic and pharmaceutical formulations, such ascreams, lotions, gels and ointments are commonly used by consumers, newforms are desirable, in order to achieve better control of theapplication, while maintaining or bestowing the skin beneficialproperties of such products. Thus, the development of a new composition,having breakable foam consistency when extruded out of a container andliquid properties when applied onto the skin is advantageous. Ideally afoam should contain hydrophobic substances (solvents), which can act asemollients and provide the skin with soothing and nourishing properties.However, such hydrophobic solvents are difficult to formulate into alather-producing or foam-producing product because the hydrophobicsolvents interfere with the lather forming ability of the surfactant.Furthermore, addition of oils and other emollients to topicalformulations can result in an unpleasant or annoying skin residue.

Use of emulsions in foam compositions is known. Emulsion systems providea two-phase system including lipophilic or hydrophobic components in onephase and hydrophilic components in the second phase. The foamedemulsion typically is an oil-in-water emulsion in which the hydrophobiccomponent is dispersed in the aqueous continuous phase. Surfactants forreducing surface tension and emulsifiers for improving foam stabilityare included in the foam composition.

Foams and, in particular, foam emulsions are complicated systems whichdo not form under all circumstances. Slight shifts in foam emulsioncomposition, such as by the addition of active ingredients, maydestabilize the foam. Furthermore, many emulsions do not provide thehigh foam capacity, foam stability and/or fast-breaking action understress or temperatures that are desired in a topical foam composition.

A particularly desirable type of oil-containing foam is such wherein allor part of the oil phase comprises silicone oil. Silicone oil is knownfor its skin protective features and its incorporation in topicalproducts is beneficial. However, it is not obvious to produce siliconeoil-based foams, since many silicone oils possess anti-foamingproperties.

U.S. Pat. No. 6,126,920 discloses treatment of various skin diseases,and in particular, scalp psoriasis, using a foamable pharmaceuticalcomposition containing a corticosteroid active substance, an aliphaticalcohol, water, a fatty alcohol, a surface-active agent, a propellantand a buffering agent. The foamable composition contains 40-90% w/wcomposition of an aliphatic alcohol. U.S. Pat. No. 6,126,920 is typicalof many compositions that use aliphatic alcohols in the foamcomposition. The alcohol promotes fast drying and thereby attempts toaddress the sticky feeling left by many topical formulations afterapplication; however, alcohols, and in particular the methyl, ethyl andisopropyl alcohols preferred in the '920 patent, are defatting agentsand may cause skin to become dry and cracked. Hence, the presence ofaliphatic alcohol in a therapeutic foam for external topicaladministration as taught in U.S. Pat. No. 6,126,920 is undesirable.

U.S. Pat. No. 5,536,743 to Borgman describes a buffered non-flowingcomposition suitable for the treatment of bacterial vaginosis whichcontains metronidazole. Suitable formulations include oil-in-wateremulsions including an internal oil phase of about 10-40 wt % oil andanionic, cationic or nonionic surfactants. Suitable components of theoleaginous phase include long chain alcohols, esters, and acids,vegetable and animal oils and waxes. No other stabilizing agents aredisclosed for use in foam aerosol compositions.

EP 0,598,412 describes a composition that is useful for skin protectionagainst drying and harsh environmental substances. The protection isderived from the inclusion of poly(tetrafluoroethylene) (PTFE) in thecomposition. The composition includes low levels of both hydrophilicemollients and hydrophobic emollients. The compositions include highlevels of surfactants, including ionic surfactants, and co-emulsifiersresulting in thick emulsions which are not flowable, and thus providingproducts which are inefficient foamers (or non-foaming) and too thickfor spreading over large skin areas.

U.S. Pat. No. 6,423,323 describes an aqueous foam emulsion. Thecomposition includes a hydrophobic phase including fatty acids,emulsifiers and co-emulsifiers, and an aqueous phase containinghydrophilic moisturizers and emulsifiers. An optional ingredientaccording to U.S. Pat. No. 6,423,323 is one or more refattingsubstances, in preferable concentrations of 0.5 to 2%, if the product isto be used for normal skin; and 3 to 6% for dry skin. Addition of highlevels of co-emulsifiers such as fatty alcohols and fatty acids suggestthat the foam is not stable. No other stabilizing agents are disclosed.

U.S. Pat. No. 5,635,469 describes a foamable cleansing liquidcomposition comprising about 0.05% to about 10% of an emollient, inaddition to cleansing surfactants, humectants and water soluble cationicor nonionic polymers, but no propellants. Low density foams are achievedusing a novel non-aerosol foam dispenser. The foaming is achieved byoperating a manual pump, which is not convenient for operation.Emollients and humectants are included to improve the level of hydrationand/or lipid content of the skin. However, the patent notes thatemollients and humectants interfere with the lather forming ability ofthe surfactant.

U.S. Pat. No. 6,113,888 teaches a single water phase compositioncomprising a self-tanning agent, a nitrogen-free polymer, anitrogen-free surfactant, and water.

U.S. Pat. No. 5,679,324 to Lisboa pertains to an aerosol foamablefragrance composition, translucent in its pre-dispensed state, whichforms a fast breaking foam. Apparently the foam breaks spontaneouslyupon discharging from an aerosol container (with no need of any rubbingor sheer force application), thus, making is impractical for spreadingover a skin surface. The composition contains surfactant, a propellant,a fragrance, a thickener, and a cosmetic vehicle (preferably water)wherein the ratio of the surfactant to propellant is from about 1:1 toabout 1:10. Emollients including silicone oils, mineral oils andhydrocarbon oils may be included.

U.S. Pat. No. 6,251,369 discloses foamable dental fluoride compositionscontaining a water-soluble fluoride component, whereby said compositionsinclude an oil in water emulsion. However, the patent fails to specifythe identity or concentration of the oil component of the emulsion; andnone of the compositions presented in the examples contain any oilcomponent.

U.S. Pat. No. 5,961,957 describes a barrier foam composition comprisingfrom 70 to 90% of water, from 7 to 9% of butane, from 2 to 4% ofglyceryl monostearate, from 1.5 to 3.50% of dimethicone copolyol (awater-soluble silicone compound), from 1 to 3% of propane, from 0.5 to2.5% of lanolin, from 0.5 to 2.5% of stearic acid and from 0.05 to 1.05%of at least one of methylchloroisothiazolinone andmethylisothiazolinone.

A few dermatological foam products are available on the market.

Olux™ Foam, produced by Connetics, Inc., contains clobetasol propionate.Each gram of Olux™ Foam contains 0.5 mg clobetasol propionate, USP, in athermolabile foam, which consists of ethanol (60%), purified water,propylene glycol, cetyl alcohol, stearyl alcohol, polysorbate 60, citricacid, and potassium citrate. It is dispensed from an aluminum canpressurized with a hydrocarbon propellant (propane/butane). Luxiq™ isanother corticostroid foam medication, containing 1.2 mg betamethasonevalerate per gram, in a vehicle, comprising ethanol (60.4%), purifiedwater, propylene glycol, cetyl alcohol, stearyl alcohol, polysorbate 60,citric acid, and potassium citrate, and pressurized with a hydrocarbonpropellant.

Cortifoam, a hydrocortisone acetate rectal foam is produced by SchwartzPharma GmbH, wherein the hydrocortisone is present at 10% in a foamvehicle. Nonmedicinal ingredients of Cortifoam include cetyl alcohol,ethoxylated stearyl alcohol, methylparaben, polyoxyethylene-10 stearylether, propylene glycol, propylparaben, triethanolamine, water, andinert propellants, isobutene, and propane.

Thus, foam compositions for topical treatment, containing higherconcentrations of oils, and do not comprise alcohol are still desirable.Foam compositions that are robust and suitable for inclusion of a widerange of active ingredients are desired.

SUMMARY OF THE INVENTION

Despite the commonly known fact that hydrophobic solvents are difficultto formulate into a lather-producing or foam-producing product and thataddition of conventional hydrophobic solvents interferes with the latherforming ability of the surfactant, we have surprisingly discovered aseries of foamable carrier compositions, which, upon admixing with aliquefied gas propellant in an aerosol container, produces a foamablecomposition that is suitable for topical administration. Upon dischargefrom an aerosol container, the composition forms a breakable foam, whichis rich and creamy in appearance, and show very fine bubble structure.The foam does not break down immediately upon discharge, however, itcollapses to spread easily onto a skin area upon slight rubbing.

In one or more embodiments of the present invention, the alcohol-freecosmetic or pharmaceutical foamable carrier composition includes water,a liquid, non-volatile hydrophobic solvent, a foam adjuvant agentselected from the group consisting of fatty acids and fatty alcohols, asurface-active agent and a water gelling agent. Such foamable carriers,when placed in an aerosol container and combined with a liquefied gaspropellant, create an oil in water emulsion, which, upon release fromthe aerosol container, provides a therapeutically beneficial foamproduct. The foam retains its structure for a time sufficient for a userto apply and to rub the foam into the skin. The foam has a very lowyield strength and, hence, it breaks upon touch and makes rubbing easyand efficient, and its application even.

In one or more embodiments of the present invention, the foamablecarrier composition the hydrophobic solvent content is about 2-5% andhas a composition as follows:

Class A Composition:

-   -   about 2-5% hydrophobic solvent;    -   about 80-98% water;    -   about 0.1% to 5% foam adjuvant agent;    -   about 0.1% to 5% surface-active agent; and    -   about 0.1% to 5% water gelling agent.

In one or more embodiments of the present invention, the foamablecomposition the hydrophobic solvent content is about 5-10% and has acomposition as follows:

Class B Composition:

-   -   about 5-10% hydrophobic solvent;    -   about 75-95% water;    -   about 0.1% to 5% foam adjuvant agent;    -   about 0.1% to 5% surface-active agent; and    -   about 0.1% to 5% water gelling agent.

In one or more embodiments of the present invention, the foamablecomposition the hydrophobic solvent content is about 10-20% and has acomposition as follows:

Class C Composition:

-   -   about 10-20% hydrophobic solvent;    -   about 60-90% water;    -   about 0.1% to 5% foam adjuvant agent;    -   about 0.1% to 5% surface-active agent; and    -   about 0.1% to 5% water gelling agent.

In one or more embodiments of the present invention, the foamablecomposition the hydrophobic solvent content is about 20-75% and has acomposition as follows:

Class A Composition:

-   -   about 20-75% hydrophobic solvent;    -   about 25-75% water;    -   about 0.1% to 5% foam adjuvant agent;    -   about 0.1% to 5% surface-active agent; and    -   about 0.1% to 5% water gelling agent.

All % values are provided on a weight (w/w) basis, based on thecomposition with out propellant (unless otherwise specified).

The cosmetic or pharmaceutical foamable carrier composition is liquid.The foamable of the present invention does not contain short chainaliphatic alcohols, making it non-irritating and non-drying. Alcoholspenetrate the skin's protective barrier and break down the intercellularmatrix. In a recent publication by the American Academy of Dermatology(AAD), titled “Facing the Facts about Skin Care Products” it is stated“[i]ndividuals with dry skin should avoid astringents and any productwith alcohol because they easily strip away moisture from the skin”(see: www.aad.org/PressReleases FacingFacts.html). Another AADpublication, titled “Sensitive About Your Skin?”, recommends to “[a]voidsolvents that penetrate the skin including, propylene glycol andethanol” (see: www.aad.org/PressReleases/sensitive.html).

The alcohol-free foam carrier is formulated as an oil-in-water orwater-in-oil emulsion, so that it is suitable for inclusion of eitherwater-soluble and oil soluble active agents (or both). The foamablecarrier composition of the present invention, when admixed with apropellant substance in an amount of about 5-25% by weight of the totalcomposition in an aerosol container, produces lightweight breakablefoam, suitable for facile application onto the skin, and other bodyareas, which may accept topically-applied products. Since thepropellant, in the pressurized container is in liquid state, uponadmixing the foamable carrier composition with the propellant, a stableemulsion, comprising the oil and the propellant (jointly as the “oilphase” component of such emulsion) is formed.

In one or more embodiments of the present invention, an alcohol-freecosmetic or pharmaceutical product is provided. The product includes afoam carrier composition according to one or more embodiments of thepresent invention and an active cosmetic or pharmaceutical ingredient ina therapeutically effective concentration. Cosmetic and pharmaceuticalagents can be included in each of the compositions described above andin the detailed description that follows. Pharmaceutical products areintended for topical treatment of human and animal skin disorders, orany other disorder, that requires topical application of a drug.Cosmetic products are intended for beautifying the skin and improvingits appearance.

Cosmetic and medical disorders that are best treated using thealcohol-free foam carrier and the alcohol-free cosmetic orpharmaceutical product are identified, and the advantages of suchcarrier and products is demonstrated as compared to currently availableoptions.

The foam of the present invention is advantageous to current options,for one or more of the following reasons:

-   -   (1) The foam is lightweight and thus, economical.    -   (2) The foam contains a hydrophobic solvent, in any desirable        concentration, which provides a refatting and skin soothing        effect, as well as a carrier for hydrophobic active agents.    -   (3) The foam contains silicone oil in a therapeutically        effective concentration    -   (4) The foam includes active agent, both water soluble and oil        soluble.    -   (5) The foam is easily spreadable, allowing treatment of large        areas such as the arms, back, legs and the breast.    -   (6) Due to its flow properties, it spreads effectively into        folds and wrinkles, providing uniform distribution of the active        agent without the need of extensive rubbing and absorbs into the        skin.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the present invention and many of itsadvantages will be understood by reference to the following detaileddescription when considered in connection with the following drawings,which are presented for the purpose of illustration only are notintended to limit the scope of the appended claims, and in which:

FIG. 1 illustrates the improvement in the treatment of psoriasis usingBethasone valerate 0.12% foam; and

FIG. 2 illustrates the improvement in the treatment of atopic dermatitisusing Bethasone vale rate 0.12% foam.

DETAILED DESCRIPTION OF THE INVENTION

Hydrophobic Solvent

A hydrophobic solvent according to the present invention is a liquidmaterial having solubility in distilled water at ambient temperature ofless than about 1 gm per 100 mL, more preferable less than about 0.5 gmper 100 mL, and most preferably less than about 0.1 gm per 100 mL. It isliquid at ambient temperature.

The total content of hydrophobic solvent may vary from 2% to 75% (w/w)of the foamable composition. However, different ranges (herein“composition classes A-D”) have been designated, in order to facilitatea choice of an appropriate class, according to the anticipated cosmeticor pharmaceutical need. As a rule of thumb, higher hydrophobic solventconcentrations are more appropriate for the treatment of dry skin,and/or for the treatment of a disease, which is more responsive to drugsdelivered in an oily vehicle. Likewise, the higher oil-contentcomposition classes provide an enhanced occlusive effect, which in turninduces the skin penetration of an active agent. Another considerationrelates to user acceptance of a product containing a high concentrationof the hydrophobic solvent (from about 25% of the composition), whichwould leave some oily feeling post-application. Thus, a particularcomposition of the present invention is selected having a hydrophobicsolvent concentration in view of the target population and its specificneeds.

In one or more embodiments of the present invention, the hydrophobicsolvent is mineral oil. Mineral oil (Chemical Abstracts Service Registrynumber 8012-95-1) is a mixture of aliphatic, naphthalenic, and aromaticliquid hydrocarbons that are derived from petroleum. It is typicallyliquid; its viscosity is in the range of about 35 CST to about 100 CST(at 40° C.), and its pour point (the lowest temperature at which an oilcan be handled without excessive amounts of wax crystals forming) isbelow 0° C. By contrast, white petrolatum, also termed “Vaseline”, isdisadvantageous, due to its waxy nature. It is known to leave waxy andsticky feeling after application and occasionally stain cloths. Thus,white petrolatum and other semi-solid oils are not a preferredhydrophobic solvent according to the present invention.

Yet another preferred hydrophobic solvents are liquid oils fromvegetable, marine or animal sources. By way of example, the unsaturatedoil may be selected from the group consisting of olive, corn, soybean,canola, cottonseed, coconut, sesame, sunflower, borage seed, syzigiumaromaticum, hempseed, herring, cod-liver, salmon, flaxseed, wheat germand evening primrose oils and mixtures thereof, at any proportion.

A particularly preferred class of oils includes polyunsaturated oils,e.g., esters, and in particular glyceryl esters, of omega-3 and omega-6fatty acids. Examples of such polyunsaturated fatty acids are linoleicand linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA). Thus, in one or more embodimentsof the present invention the hydrophobic solvent includes at least 6% byweight foamable composition of an oil selected from omega-3 oil, omega-6oil, and mixtures thereof.

Another class of oils suitable for use as a phydrophobic solvent isliquid hydrophobic plant-derived oils, or essential oils, e.g.“therapeutic oils” containing active biologically occurring moleculesthat have a therapeutic effect when applied topically. Examples of suchoils include rosehip oil, which contain retinoids and is known to reduceacne and post-acne scars, and tea tree oil, which possess antibacterial,antifungal and antiviral properties. Other examples of essential oilsare oils of basil, camphor, cardamom, carrot, citronella, clary sage,clove, cypress, frankincense, ginger, grapefruit, hyssop, jasmine,lavender, lemon, mandarin, marjoram, myrrh, neroli, nutmeg, petitgrain,sage, tangerine, vanilla, verbena, as well as any other therapeuticallybeneficial oil, know in the art of herbal medication.

In one or more embodiments of the present invention, the hydrophobicsolvent is an “emollient”. An emollient is a hydrophobic agent thatsoftens, smoothens and improves lipid content of the skin or othermucous membranes. In one or more embodiments of the present invention,the emollient is a liquid. Without derogating the generality of thisdefinition, examples of suitable emollients for use include isostearicacid derivatives, isopropyl palmitate, lanolin oil, diisopropyldimerate, diisopropyl adipate, dimethyl isosorbide, maleated soybeanoil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetylricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetylacetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate,wheat germ glycerides, arachidyl propionate, myristyl lactate, decyloleate, propylene glycol ricinoleate, isopropyl lanolate,pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate,hydrogenated coco-glycerides, isononyl isononanoate, isotridecylisononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol,octyl hydroxystearate and mixtures thereof. Other examples of othersuitable emollients can also be found in the Cosmetic Bench Reference,pp. 1.19-1.22 (1996). In one or more embodiments, the hydrophobicsolvent is a mixture of a mineral oil or silicone oil and an emollient.

In one or more embodiments of the present invention, silicone oil is acomponent of the hydrophobic solvent. Silicone oils are used in thefoamable compositions due to their known skin protective and occlusiveproperties. Suitable silicone oils for use in the invention includenon-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. These arepreferably chosen from cyclic or linear polydimethylsiloxanes containingfrom about 3 to about 9, preferably from about 4 to about 5, siliconatoms. Volatile silicones such as cyclomethicones can also be used.Water-soluble silicones, such as dimethicone copolyol are not includedin the definition of silicone oils (as hydrophobic solvents) accordingto the present invention.

In one or more embodiments of the present invention, the compositioncomprises at least 2% (w/w foamable composition) silicone oil, alone oras part of the hydrophobic solvent. Yet, in other embodiments, thecomposition comprises at least 5% (w/w) silicone oil alone or as part ofthe hydrophobic solvent.

The hydrophobic solvent of the present invention may comprise a mixtureof two or more of the above hydrophobic solvents in any proportion.

Foam Adjuvant Agents

Foam adjuvants are included in the foamable compositions of the presentinvention to increase the foaming capacity of surfactants and/or tostabilize the foam. In one or more embodiments of the present invention,the foam adjuvant agents includes fatty alcohols having 15 or morecarbons in their carbon chain, such as cetyl alcohol and stearyl alcohol(or mixtures thereof). Other examples of fatty alcohols are arachidylalcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well asalcohols with longer carbon chains (up to C50). Fatty alcohols, derivedfrom beeswax, including a mixture of alcohols, a majority of which hasat least 20 carbon atoms in their carbon chain, are especially wellsuited as foam adjuvant agents according to the present invention. Theconcentration of the fatty alcohol, required to support the foam systemis inversely related to the length of its carbon chains.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have at least one double bond. A further class of foam adjuvantagent according to the present invention comprises a long chain fattyalcohol or fatty acid, wherein the carbon atom chain is branched. Thecarbon chain of the fatty acid or fatty alcohol can be substituted witha hydroxyl group, such as 12-hydroxy stearic acid.

The foam adjuvant agent according to one or more embodiments of thepresent invention includes a mixture of fatty alcohols, fatty acids andhydroxy fatty acids and derivatives thereof in any proportion, providingthat the total amount is 0.1% to 5% (w/w) of the carrier mass. Morepreferably, the total amount is 0.4%-2.5% (w/w) of the carrier mass.

While fatty alcohols and fatty acids serve to stabilize the resultantfoam composition, they often provide additional therapeutic properties.Long chain saturated and mono unsaturated fatty alcohols, e.g., stearylalcohol, erycyl alcohol, arachidyl alcohol and docosanol have beenreported to possess antiviral, anti infective, anti-proliferative andanti-inflammatory properties (U.S. Pat. No. 4,874,794). Longer chainfatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol,octacosanol, triacontanol, etc. are also known for their metabolismmodifying properties and tissue energizing properties. Long chain fattyacids have also been reported to possess anti-infective characteristics.Thus, the pharmaceutical or cosmetic carrier, containing the foamadjuvant agent of the present invention provides an extra therapeuticbenefit in comparison with currently used vehicles, which are inert andnon-active.

Surface-Active Agents

Surface-active agents, according to the present invention include anyagent linking oil and water in the composition.

The surface-active agent is suitably selected from anionic, cationic,nonionic, zwitterionic, amphoteric and ampholytic surfactants, as wellas mixtures of these surfactants. Such surfactants are well known tothose skilled in the pharmaceutical and cosmetic formulation art.Nonlimiting examples of possible surfactants include polysorbates, suchas polyoxyethylene (20) sorbitan monostearate (Tween 60) andpoly(oxyethylene) (20) sorbitan monooleate (Tween 80); poly(oxyethylene)(POE) fatty acid esters, such as Myrj 45, Myq 49 and Myrj 59;poly(oxyethylene) alkylyl ethers, such as poly(oxyethylene) cetyl ether,poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether,polyethylene glycol cetyl ether, brij 38, brij 52, brij 56 and brij W1;sucrose esters, partial esters of sorbitol and its anhydrides, such assorbitan monolaurate and sorbitan monolaurate; mono or diglycerides,isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyltaurate, sodium lauryl sulfate, triethanolamine lauryl sulfate andbetaines.

A combination of surface active agents is possible. Any surface-activeagent or combinations thereof may be used as surface-active agent.According to one or more embodiments of the present invention, thesurface-active agent (or agents) has an HLB of higher than 9.

In one or more embodiments of the present invention, the surface-activeagent is selected from the groups of non ionic surfactants, cationicsurfactants, amphoteric and zwitterionic surfactants, and, inparticular, the surface-active agent is a non-ionic surfactant. Ionicsurfactants (including cationic, anionic, amphotheric and zwitterionicsurfactants) are known to be skin irritants. Therefore, non-ionicsurfactants are preferred in applications including sensitive skin suchas found in most dermological disorders. We have surprisingly found thatnon-ionic surfactants alone provide foams of excellent quality, i.e. ascore of “E” according to the grading scale discussed below.

In one or more embodiments of the present invention, the surface activeagent is solely non-ionic, comprising one or more non-ionic surfactants.

In one or more embodiments of the present invention, the surface activeagent include a ratio of non-ionic surfactants to ionic surfactants inthe range of 100:1 to 6:1; in some embodiments the non-ionic to ionicsurfactant ratio is greater than 6:1, or greater than 8:1; or greaterthan 14:1, or greater than 16:1, or greater than 20:1.

Exemplary non-ionic surfactants include polyethoxylated fatty acids,fatty acid diesters, polyethylene glycol glycerol fatty acid esters,alcohol-oil transesterification products, polyglycerized fatty acids,sterol and sterol derivatives, polyethylene glycol sorbitan fatty acidesters, polyethylene glycol alkyl ethers, sugar esters, polyethyleneglycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers,sorbitan fatty acid esters and lower alcohol fatty acid esters.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Exemplary monoesters include esters of lauric acid, oleicacid, and stearic acid, e.g., PEG-8 laurate, PEG-8 oleate, PEG-8stearate, PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate,PEG-12 oleate, PEG-15 oleate, PEG-20 laurate and PEG-20 oleate.Polyethylene glycol fatty acid diesters suitable for use as non-ionicsurfactants in the compositions of the present invention include PEG-20dilaurate, PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate andPEG-32 dioleate. Suitable polyethylene glycol glycerol fatty acid estersinclude PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-40glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryl oleate.

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholswith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35),PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). Preferred hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil® b M 2735 CS), PEG-8 corn oil (Labrafil® WL2609 BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almondglycerides (Crovol A40). The latter two surfactants are reported to haveHLB values of 10, which is generally considered to be the approximateborder line between hydrophilic and hydrophobic surfactants.

Alcohol-oil transesterification derivatives of oil soluable vitamins(e.g., vitamins A, D, E, K, etc.), such as tocopheryl PEG-100 succinate(TPGS, available from Eastman), are also suitable surfactants.

Polyglycerol esters of fatty acids are also suitable non-ionicsurfactants for the present invention. Among the polyglyceryl fatty acidesters, exemplary use hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO), andpolyglyceryl-10 trioleate. Preferred hydrophilic surfactants includepolyglyceryl-10 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate(Nikkol Decaglyn 1-O), and polyglyceryl-10 mono, dioleate (Caprol® PEG860), Polyglyceryl polyricinoleates (Polymuls) are hydrophilic andhydrophobic surfactants of this class.

Sterols and derivatives of sterols are suitable surfactants for use inthe present invention. These surfactants can be hydrophilic orhydrophobic. Preferred derivatives include the polyethylene glycolderivatives. An exemplary hydrophobic surfactant in this class ischolesterol. An exemplary hydrophilic surfactant in this class is PEG-24cholesterol ether (Solulan C-24).

A variety of PEG-sorbitan fatty acid esters are suitable for use asnon-ionic surfactants in the present invention. In general, thesesurfactants are hydrophilic, although several hydrophobic surfactants ofthis class can be used. Among the PEG-sorbitan fatty acid esters,exemplary hydrophilic surfactants include PEG-20 sorbitan monolaurate(Tween-20), PEG-20 sorbitan monopalmitate (Tween-40), PEG-20 sorbitanmonostearate (Tween-60), and PEG-20 sorbitan monooleate (Tween-80).

Ethers of polyethylene glycol and alkyl alcohols are suitable non-ionicsurfactants for use in the present invention. Exemplary hydrophobicethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

The polyoxyethylene-polyoxypropylene (POE-POP) block copolymers are aunique class of polymeric surfactants. The unique structure of thesurfactants, with hydrophilic POE and hydrophobic POP moieties inwell-defined ratios and positions, provides a wide variety ofsurfactants suitable for use in the present invention. These surfactantsare available under various trade names, including Synperonic PE series(ICI), Pluronic® series (BASF), Emkalyx, Lutrol (BASF), Supronic,Monolan, Pluracare, and Plurodac. The generic term for these polymers is“poloxamer” (CAS 9003-11-6). Exemplary hydrophilic surfactants of thisclass include Poloxamers 108, 188, 217, 238, 288, 338, and 407.Exemplary hydrophobic surfactants in this class include Poloxamers 124,182, 183, 212, 331, and 335.

Sorbitan esters of fatty acids are suitable non-ionic surfactants foruse in the present invention. Among these esters, preferred hydrophobicsurfactants include sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, and sorbitan tristearate.

Esters of lower alcohols (C₂ to C₄) and fatty acids (C₈ to C₁₈) aresuitable non-ionic surfactants for use in the present invention. Amongthese esters, preferred hydrophobic surfactants include ethyl oleate(Crodamol EO), isopropyl myristate (Crodamol IPM), and isopropylpalmitate (Crodamol IPP).

In one or more embodiments of the present invention, the surface-activeagent comprise mono-, di- and tri-esters of sucrose with food fattyacids (sucrose esters), prepared from sucrose and methyl and ethylesters of food fatty acids or by extraction from sucroglycerides.Exemplary sucrose esters include sucrose monopalmitate and sucrosemonolaurate. Suitable sucrose esters include those having a highmonoester content, which have higher HLB values.

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an anionic surfactant (such as sodium laurylsulphate) is employed, at a ratio of between 1:1 and 20:1, or at a ratioof 4:1 to 10:1. The resultant foam has a low specific gravity, e.g.,less than 0.1 g/ml, which upon rubbing (shear stress) onto the skincollapses easily, to allow facile absorption.

Unlike prior art foamable compositions, the total surfactant employed toobtain a foam that is stable, of low specific gravity and has a finebubble structure is low. Lower surfactant levels, particularly of ionicsurfactants, are preferred to reduce skin irritations. Total surfactantis in the range of 0.1 to 5.0 wt % of the foamable composition, and istypically less than 2 wt %, or even less than 1 wt %.

Water Gelling Agents

The water gelling agent according to one or more embodiments of thepresent invention stablizes the acqueons phase by, for example,increasing viscosity and linking capability. Exemplary water gellingagents that can be used in accordance with one or more embodiments ofthe present invention include for example, but are not limited to,naturally-occurring polymeric materials such as, locust bean gum, sodiumalginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gumsodium alginate, xanthan gum, quince seed extract, tragacanth gum,starch, chemically modified starches and the like, semi-syntheticpolymeric materials such as cellulose ethers (e.g. hydroxyethylcellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose), polyvinylpyrrolidone, polyvinylalcohol, guargum, hydroxypropyl guar gum, soluble starch, cationic celluloses,cationic guars and the like and synthetic polymeric materials such ascarboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcoholpolyacrylic acid polymers, polymethacrylic acid polymers, polyvinylacetate polymers, polyvinyl chloride polymers, polyvinylidene chloridepolymers and the like. Mixtures of the above compounds are contemplated.

Further exemplary water gelling agents include the acrylic acid/ethylacrylate copolymers and the carboxyvinyl polymers sold, for example, bythe B.F. Goodrich Company under the trademark of Carbopol Registered TMresins. These resins consist essentially of a colloidal water-solublepolyalkenyl polyether crosslinked polymer of acrylic acid crosslinkedwith from 0.75% to 2% of a crosslinking agent such as polyallyl sucroseor polyallyl pentaerythritol. Examples include Carbopol 934, Carbopol940, Carbopol 950, Carbopol 980, Carbopol 951 and Carbopol 981. Carbopol934 is a water-soluble polymer of acrylic acid crosslinked with about 1%of a polyallyl ether of sucrose having an average of about 5.8 allylgroups for each sucrose molecule.

The gelling agent is present in an amount in the range of about 0.1% toabout 5.0 wt % of the foamable composition. In one or more embodiments,it is typically less than 1 wt % of the foamable composition.

“Alcohol Free”

Unlike the composition disclosed in U.S. Pat. No. 6,126,920, whichcontains a 40-90 wt % aliphatic alcohol, the composition of the presentinvention does not contain such amount alcohols. For the purpose of thepresent application, the term “alcohol free” shall mean that thecomposition contains no more than an incidental amount of an aliphaticalcohol, e.g. less than about 7.5% of any aliphatic alcohol, having oneto six carbon atoms in their carbon backbone, or no more than 7.5% ofany mixture of such aliphatic alcohols. Alcohols at these low levels arenot considered to have a negative effect on skin or mucous membranes. Inone or more embodiments, the foamable compositions do not contain anyalcohol.

Optional Ingredients

The pharmaceutical or cosmetic foam carrier of the present invention mayfurther optionally comprise a variety of pharmaceutical or cosmeticingredients, which are added in order to fine-tune the consistency ofthe formulation, protect the formulation components from degradation andoxidation and bestow their cosmetic acceptability. Such excipients, maybe selected, for example, from the group consisting of diglycerides,triglycerides, stabilizing agents, antioxidants, humectants, flavoring,colorant and odorant agents and other formulation components, used inthe art of pharmaceutical and cosmetic formulary. A pharmaceutical orcosmetic composition manufactured using the foam carrier according tothe present invention is very easy to use. When applied onto theafflicted body surface of humans or animals, it is in a foam state,allowing free application without spillage. Upon further application ofa mechanical force, e.g., by rubbing the composition onto the bodysurface, it freely spreads on the surface and is rapidly absorbed.

Propellant Aerosol

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable carrier. The propellant makes up about 5-25 wt % of thefoamable carrier. Examples of suitable propellants include volatilehydrocarbons such as butane, propane, isobutane or mixtures thereof, andfluorocarbon gases.

Composition and Foam Physical Characteristics

1. Composition Flow Properties:

It is important to have a composition, including water, hydrophobicsolvents, formulation excipients and propellant, in a stable emulsion,which ascertain acceptable shelf-life of the product.

Yet, another crucial property is that said composition has to be freeflowing, since otherwise, it cannot flow through the dip-tube of theaerosol container and create acceptable foam. It has been noted that inthe context of the composition of the present invention, compositionscomprising semi-solid hydrophobic solvents, e.g., white petrolatum, areexcessively viscous and demonstrate poor flowability.

The combination of a surface active agent, foaming adjuvant and watergelling agent according to one or more embodiments of the inventionprovides a low specific gravity foam having superior flow properties andsheer breakability (among other attributes). According to one or moreembodiments of the present invention, the total amount of surface activeagent, foaming adjuvant and water gelling agent, in combination does notexceed 8% (w/w) of foamable composition. In other embodiments, thecombined amounts of surface active agent, foaming adjuvant and watergelling agent is less than 5% (w/w) of foamable composition. The lowsolids content improves the flow properties of the foam, reducesunpleasant skin residue and reduces the cost of manufacture. As isdemonstrated herein, the foam quality and foam breakability isexcellent, despite the low levels of these components in the foam.

2. Foam Properties:

The following scale for foam quality is used to evaluate foams.

E (excellent): very rich and creamy in appearance, does not show anybubble structure or shows a very fine (small) bubble structure.

G (good): rich and creamy in appearance, very small bubble size, “dulls”more rapidly than an excellent foam.

FG (fairly good): a moderate amount of creaminess noticeable, bubblestructure is noticeable.

F (fair): very little creaminess noticeable, larger bubble structurethan a “fairly good” foam.

P (poor): no creaminess noticeable, large bubble structure.

VP (very poor): dry foam, large very dull bubbles, difficult to spreadon the skin.

Foams, adequate for topical administration according to the presentinvention have to be of quality grade E or G, upon release from theaerosol container. Smaller bubbles mean more stable foam, which does notcollapse spontaneously immediately upon discharge from the container.The finer foam structure looks and feels smoother, thus increasing itsusability and appeal.

A crucial aspect of foam properties, according to the present inventionis breakability. Sheer-force breakability of the foam, as attained bythe composition of the present invention is clearly advantageous tothermally-induced breakability, present, for example in U.S. Pat. No.6,126,920, and the respective Olux and Luxiq products, as demonstratedby the fact that according to the use instructions of Olux and Luxiq,the foam cannot be applied on the hand and afterwards delivered to theafflicted area, since it immediately collapses upon exposure to skintemperature.

Yet, another important property is specific gravity of the foam, asmeasured upon release from the aerosol can. Typically, foams accordingto the present invention have specific gravity of less than 0.1 g/mL andmore preferably, less than 0.05 g/mL.

Fields of Pharmaceutical Applications

By including an appropriate therapeutic agent in the foamable carrier,the foam composition of the present invention is useful in the therapyof a variety of dermatological disorders (also termed “dermatoses”),including, in a non-limiting exemplary manner:

Dermatitis

-   -   Contact Dermatitis    -   Atopic Dermatitis    -   Seborrheic Dermatitis    -   Nummular Dermatitis    -   Chronic Dermatitis Of The Hands And Feet    -   Generalized Exfoliative Dermatitis    -   Stasis Dermatitis    -   Lichen Simplex Chronicus

Bacterial Infections

-   -   Cellulitis    -   Acute Lymphangitis    -   Lymphadenitis    -   Erysipelas    -   Cutaneous Abscesses    -   Necrotizing Subcutaneous Infections    -   Staphylococcal Scalded Skin Syndrome    -   Folliculitis    -   Furuncles    -   Hidradenitis Suppurativa    -   Carbuncles    -   Paronychial Infections    -   Erythrasma

Fungal Infections

-   -   Dermatophyte Infections    -   Yeast Infections

Parasitic Infections

-   -   Scabies    -   Pediculosis    -   Creeping Eruption

Viral Infections

Disorders of Hair Follicles and Sebaceous Glands

-   -   Acne    -   Rosacea    -   Perioral Dermatitis    -   Hypertrichosis (Hirsutism)    -   Alopecia, including male pattern baldness, alopecia greata,        alopecia universalis and alopecia totalis    -   Pseudofolliculitis Barbae    -   Keratinous Cyst

Scaling Papular Diseases

-   -   Psoriasis    -   Pityriasis Rosea    -   Lichen Planus    -   Pityriasis Rubra Pilaris

Benign Tumors

-   -   Moles    -   Dysplastic Nevi    -   Skin Tags    -   Lipomas    -   Angiomas    -   Pyogenic Granuloma    -   Seborrheic Keratoses    -   Dermatofibroma    -   Keratoacanthoma    -   Keloid

Malignant Tumors

-   -   Basal Cell Carcinoma    -   Squamous Cell Carcinoma    -   Malignant Melanoma    -   Paget's Disease Of The Nipples    -   Kaposi's Sarcoma

Reactions To Sunlight

-   -   Sunburn    -   Chronic Effects of Sunlight    -   Photosensitivity

Bullous Diseases

-   -   Pemphigus    -   Bullous Pemphigoid    -   Dermatitis Herpetiformis    -   Linear Immunoglobulin A Disease

Pigmentation Disorders

-   -   Hypopigmentation        -   Vitiligo        -   Albinism        -   Postinflammatory hypopigmentation    -   Hyperpigmentation        -   Melasma (chloasma)        -   Drug-induced hyperpigmentation        -   Postinflammatory hyperpigmentation

Disorders of Cornification

-   -   Ichthyosis    -   Keratosis Pilaris    -   Calluses And Corns    -   Actinic keratosis

Pressure Sores

Disorders of Sweating

Inflammatory reactions

-   -   Drug Eruptions    -   Toxic Epidermal Necrolysis    -   Erythema Multiforme    -   Erythema Nodosum    -   Granuloma Annulare

In one or more embodiments of the present invention, the foamcomposition of the present invention is useful in the therapy ofnon-dermatological disorders, which respond to transdermal delivery ofan active agent. By way of example, such disorders include localizedpain in general, as well as joint pain, muscle pain, back pain,rheumatic pain, arthritis, ostheoarthritis and acute soft tissueinjuries and sports injuries. Other disorders of this class includeconditions, which respond to hormone therapy, such as hormonereplacement therapy, transdermal nicotine administration, and otherrespective disorders, known in the art of drug delivery. The foamcomposition of the present invention is also useful in the delivery oflocal anesthetic agents.

Active Pharmaceutical Agents (Drugs)

The active pharmaceutical agents, also referred to as “drug(s)”, mayconsist of a single drug or a combination of drugs that can be dissolvedin the water phase or the hydrophobic phase of the carrier composition.Examples of such drugs are antibiotic, antibacterial, antifungal,antiviral, antiinflammatory, anesthetic, analgesic, antiallergic,corticosteroid, retinoid and antiproliferative medications and mixturesthereof at any proportion. The concentration of drugs may be adopted toexert a therapeutic effect on a disease when applied to an afflictedarea.

Antibacterial Agents

One important class of drugs comprises antibacterial agents. It is wellknown that bacterial infections are involved in a variety of superficialdisorders of the skin, eye, mucosal membrane, oral cavity, vagina andrectum. The antibacterial drug can be active against gram positive andgram-negative bacteria, protozoa, aerobic bacteria and unaerobic ones.

By way of example, the antibacterial drugs can be selected from thegroup of chloramphenicol, tetracyclines, synthetic and semi-synthesicpenicillins, beta-lactames, quinolones, fluoroquinolnes, macrolideantibiotics, metronidaziole and its derivatives and analogs,dicarboxylic acids, such as azelaic acid, slicylates, peptideantibiotics, cyclosporines and any combination thereof at atherapeutically effective concentration. Another group of antibacterialagents which is non-specific, comprises strong oxidants and free radicalliberating compounds, such as hydrogen peroxide, bleaching agents (e.g.,sodium, calcium or magnesium hypochloride and the like) iodine,chlorohexidine and benzoyl peroxide.

Antibacterial compositions according to the present invention may beused to treat infections of the skin. An example of a very common skininfection is acne, which involve infestation of the sebaceous gland withp. acnes, as well staphylococus aurus and pseudomonas. Variousantibacterial agents have been utilized to treat acne, however, theirefficacy is limited due to their low penetration into the hydrophobicenvironment of the skin layers and sebaceous glands. The composition ofthe present invention, comprising a hydrophobic component, wouldfacilitate an enhanced rate of penetration. Furthermore, the intrinsicantibacterial and antiinflammatory effects of the foam adjuvant agents,i.e., fatty alcohols and acids, provides a combined effect that shouldresult in a better therapeutic response to treatment.

The composition of the present invention is particularly useful andbeneficial in the prevention and treatment of secondary infections,accompanying skin-structure damage, such as in cuts, wounds, burns andulcers. In all such cases, the present formulation is easy to use, beingin foam state when applied and becoming liquid instantly upon rubbingonto the skin.

While being useful in the prevention and treatment of infections, theantibacterial foam of the present invention is also applicable fordecontaminating areas, afflicted with bacterial warfare organisms, suchas anthrax and smallpox.

The same advantage is expected when the composition of the presentinvention is topically applied to mucosal membranes, the oral cavity,the vagina and the rectum.

Anti-Fungal Agents

Fungal infections are another object of treatment using the compositionof the present invention. Superfidal fungal infection of the skin is oneof the commonest skin diseases seen in general practice. Dermatophytosisis probably the most common superficial fungal infection of the skin. Itis caused by a group of fungi, which are capable of metabolizing thekeratin of human epidermis, nails or hair. There are 3 genera ofdermatophytes causing dermatophytosis, i.e, microsporum, trichophytonand epidermophyton.

Candidiasis is an infection caused by the yeast like fungus candidaalbicans or occasionally other species of candida. Clinical syndromes ofcandidiasis include: (a) oral candidiasis (oral thrush); (b) candidiasisof the skin and genital mucous membrane; and (c) candida paronychia,which inflicts the nail.

The pharmaceutical composition may comprise an antifungal drug, which isactive against dermatophytes and candida, selected from the group of,but not limited to azoles, diazoles, triazoles, miconazole, fluconazole,ketoconazole, clotrimazole, itraconazole griseofulvin, ciclopirox,amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine(5FC) and any combination thereof at a therapeutically effectiveconcentration.

It is useful, for example for the treatment of tinea corporis, tineapedis, tinea rubrum, tinea unguium, tinea cruris, tinea barbae and tineaversicolor, as well as yeast Infections, such as candidiasis, andcandidal vaginitis

Anti-Viral Agents

The composition of the present invention is particularly beneficial inthe case of viral infections. Cold sores are caused by the herpessimplex Type 1 virus and are sometimes referred to as facial herpes.Mollusca are small viral growths that appear singly or in groups on theface, trunk, lower abdomen, pelvis, inner thighs, or penis. Shingles(herpes zoster), which usually only occurs once in a lifetime, appearsas a rash (clusters of blisters with a red base). It is caused by thesame virus responsible for chickenpox. Warts are a common, benign skintumor caused by viral infection.

Viral infections are currently treated with various antiviral agents, assummarized in the following table:

Chemical Drug Viruses Type Vidarabine Herpesviruses Nucleoside analogueAcyclovir Herpes simplex Nucleoside (HSV) analogue GancyclovirCytomegalovirus Nucleoside (CMV) analogue Nucleoside-analog reversetranscriptase Retroviruses Nucleoside inhibitors (NRTI): AZT(Zidovudine), (HIV) analogue ddl (Didanosine), ddC (Zalcitabine), d4T(Stavudine), 3TC (Lamivudine) Non-nucleoside reverse transcriptaseRetroviruses Nucleoside inhibitors (NNRTI): Nevirapine, (HIV) analogueDelavirdine Protease Inhibitors: Saquinavir, HIV Peptide Ritonavir,Indinavir, Nelfinavir analogue Ribavirin Broad spectrum: Triazole HCV,HSV, carboxamide measles, mumps, Lassa fever Amantadine/RimantadineInfluenza A Tricyclic strains amine Interferons Hepatitis B Protein andC

Any of the above antiviral drugs, in a therapeutically effectiveconcentration, can be incorporated in the foam composition of thepresent invention. The composition of the present invention, whichcomprises a hydrophobic solvent, would facilitate an enhanced rate ofpenetration and better topical distribution of any of the above listedantiviral drugs. Furthermore, the intrinsic antiviral effects of thefoam adjuvant agents, i.e., fatty alcohols and acids, provides acombined effect that should result in a better therapeutic response totreatment.

Antiinflammatory or Antiallergic Agents

Yet, according to another embodiment according to the present inventionthe drug is an antiinflammatory or antiallergic agent. Antiinflammatoryor antiallergic agent can be selected from the group of corticosteroids,non-steroidal antiinflammatory drugs (NSAIDs), anti-histamines,immunosuppressants and any combination thereof at a therapeuticallyeffective concentration.

The following table provides a summary of currently availablecorticosteroid agent and their typical therapeutically effectiveconcentration.

Potency Compound Formulation Very high Clobetasol proprionate Cream orointment 0.05% Halobetasol proprionate Cream or ointment 0.05% HighBetamethasone diproprionate Cream or ointment 0.05% Betamethasonevalerate Ointment 0.1% Fluocinolone acetonide Cream 0.02% HalcinonideCream or ointment 0.1% Medium Betamethasone valerate Cream 0.1%Fluocinolone acetonide Cream or ointment 0.020% Hydrocortisone valerateCream or ointment 0.2% Triamcinolone acetonide Cream, ointment, orlotion 0.1% or 0.020% Low Hydrocortisone Cream, ointment, or lotion 1.0%or 2.5%

The concentrations of corticosteroid drugs, as presented in the abovetable are provided herein only as example, and any therapeuticallyeffective concentration of such corticosteroids can be incorporated inthe composition of the present invention.

Since all corticosteroid drugs are typically hydrophobic, the carrier ofthe present invention, comprising a hydrophobic solvent, is mostsuitable as a vehicle to facilitate better topical distribution and anenhanced rate of penetration of any of the above listed drugs.Furthermore, the intrinsic antiviral, antibacterial and antiinflammatoryeffects of the foam adjuvant agents, i.e., fatty alcohols and acids,provides a combined effect that should result in a better therapeuticresponse to treatment.

Psoriasis is a very common chronic skin disease, which may be the targetof treatment using the composition of the present invention. It ismarked by periodic flare-ups of sharply defined red patches covered by asilvery, flaky surface.

Corticosteroid ointments, greasy preparations containing little or nowater, are commonly used for treating psoriasis. Their main disadvantageis in their sticky feeling, which remains so long after treatment isover. By contrast, the foam of the present invention, while comprisingconsiderable concentration of an oil (hydrophobic solvent), spreads veryeasily throughout the afflicted area and absorbs into the skin withoutleaving any untoward sensation or look. Examples of other inflammatorydisorders, which can be treated by the composition of the presentinvention, wherein the drug is a steroid are atopic dermatitis,seborrhea, seborrheic dermatitis of the face and trunk, seborrheicblepharitis, contact dermatitis, stasis dermatitis (gravitationaleczema; varicose eczema), exfoliative dermatitis (erythroderma), lichensimplex chronicus, pityriasis rosea and pemphigus.

Topical antihistaminic preparations currently available include 1% and2% diphenhydramine (Benadryl® and Caladryl®), 5% doxepin (Zonalon®)cream, phrilamine maleate, chlorpheniramine and tripelennamine,phenothiazines, promethazine hydrochloride (Phenergan®) and dimethindenemaleate. These drugs, as well as additional antihistamins can also beincorporated in the composition of the present invention.

It is pointed out that polyunsaturated fatty acids, containing omega-3and omega-6 fatty acids (e.g., linoleic and linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) are beneficial in the treatment of psoriasisand other skin inflammation conditions.

A second class of anti-inflammatory agents, which is useful in the foamof the present invention, includes the nonsteroidal anti-inflammatoryagents (NSAIDs). The variety of compounds encompassed by this group iswell-known to those skilled in the art. Specific non-steroidalanti-inflammatory agents useful in the composition invention include,but are not limited to:

1) Oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam;

2) Salicylates, such as salicylic acid, ethyl salicylate, methylsalycilate, aspirin, disalcid, benorylate, trilisate, safapryn, solprin,diflunisal, and fendosal;

3) Acetic acid derivatives, such as diclofenac, fenclofenac,indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,felbinac, and ketorolac;

4) Fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, andtolfenamic acids;

5) Propionic acid derivatives, such as ibuprofen, naproxen,benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen,indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and

6) Pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone,azapropazone, and trimethazone.

Any further steroidal and nonsteroidal compounds, having the capacity toprevent, alleviate the symptoms of, treat or cure inflammationprocesses, are generally included, as possible anti-inflammatory agents,according to the present invention.

The pharmaceutical composition of the present invention may alsocomprise an antiinflammatory or antiallergic agent, wherein said agentreduces the occurrence of pro-inflammatory cytokines or inhibits theeffect of pro-inflammatory cytokines.

Mixtures of such anti-inflammatory agents may also be employed, as wellas the dermatologically acceptable salts, esters, amides, prodrugs andderivatives of these agents.

Topical application of a foam, comprising a safe and effective dose ofan NSAID can be useful in the prevention and/or alleviation of thesymptoms of rheumatoid arthritis, osteoarthritis and pain. TopicalNSAIDs, incorporated in the foam of the present invention can be alsoused in the treatment of dermatological disorders, such as acne,rosacea, hair growth disorders, actinic keratosis and certain skincancer conditions.

Topical Anesthetics

The compositions of the present invention may contain a safe andeffective amount of a topical anesthetic. Examples of topical anestheticdrugs include benzocaine, lidocaine, bupivacaine, chlorprocaine,dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine,procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceuticallyacceptable salts thereof. Mixtures of such anesthetic agents may besynergistically beneficial.

Keratolytically Active Agents

The term “keratolytically active agent” is used herein to mean acompound which loosens and removes the stratum corneum of the skin, oralters the structure of the keratin layers of skin.

Keratolytically active agents are used in the treatment of manydermatological disorders, which involve dry skin, hyperkeratiinization(such as prsoriasis), skin itching (such as xerosis), acne and rosacea.

Suitable keratolytically active agent include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. As such, they areused in the treatment of dermatological disorders. Dihydroxy benzene andderivatives thereof have been recognized as potent keratolytic agents.Resorcinol (m-dihydroxybenzene) and derivatives thereof are used inanti-acne preparations. Hydroquinone (p-dihydroxybenzene), besides itsanti-pigmentation properties, is also keratolytic. These compounds alsoexhibit antiseptic properties. Cresols also possess bactericidal andkeratolytic properties.

Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid,retinol and retinal are another preferred class of keratolyticallyactive agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as Salicylic acid(o-hydroxybenzoic acid) and its salts and pharmaceutically acceptablederivatives, which typically possess anti-inflammatory, as well askeratolytic, activity.

Yet, another class of preferred keratolytically active agents includesurea and its derivatives.

Retinoids

Another preferred group of active agents comprise retinol, retinal, alltrans retinoic acid and derivatives, isomers and analogs thereof,collectively termed “retinoids”. Etretinate, actiretin, isotretinoin,adapalene and tazarotene are further examples of said retinoid isomersand analogs. Compositions according to the present invention, whichcontain retinoids as the active drug, can be used for the treatment ofacne, seborrhea, various dermatoses, inflammation of the skin, mucosalmembranes, vagina and the rectum, psoriasis, actinic keratosis and skincancers, by application onto the affected area.

Insecticide and Insect Repellents Agents

Insects, such as mosquitoes, biting flies, mites, gnats, fleas,chiggers, punkies, sand flies, lice and ticks can be annoying andsometimes pose a serious risk to human and animal health. In certainareas of the United States, mosquitoes can transmit diseases like equineand St. Louis encephalitis. Biting flies can inflict a painful bite thatcan persist for days, swell, and become infected. Ticks can transmitserious diseases like Lyme disease and Rocky Mountain spotted fever.

There are several types of insect repellents to use when protectingpeople and animals from flying or biting insects, spiders, ticks andmites. By way of example, these may include DEET(N,N-diethyl-m-toluamide), dimethyl phthalate, piperonyl butoxide andpermethrin. Insect repelling terpenoids, have been reported by Hwang, etal, J. Chem. Ecol., 11, 1297 (1985); and Ruledge, J. Am. MosquitoControl Assoc. 4, 414 (1988).

A particularly preferred group of insect repellents includes theterpenoid compounds, described in U.S. Pat. No. 5,411,992, including:

(1) Terpenoid-alcohol or terpene-ols are terpenoids which have at leastone hydroxyl group. Examples of terpene-ols include: C₁₀H₁₆O compounds,perillyl alcohol, carveol, myrtenol, and cis-verbenol; C₁₀H₁₈Ocompounds, myrtanol, iso-pinocampheol, dihydrocarveol, isopulegol,terpineol, terpinen-4-ol, nerol, geraniol, and linalool, and C₁₀H₂₀Ocompounds, menthol, beta-citronellol, and dihydro-myrcenol.

(2) Terpenoid-esters are terpenoids, which have at least one ester groupwhich is the product of the bonding of the hydroxyl group of aterpene-ol with an aliphatic carboxylic acid that can contain functionalgroups such as the hydroxyl or amine on the aliphatic chain. Examples ofsuitable aliphatic carboxylic acids include acetic acid, propionic acid,lactic acid, and various amino acids. Examples of terpenoid-estersinclude: carvyl acetate, carvyl propionate, and menthyl lactate.

(3) Essential oils which contain terpenoids and perfumes which containterpenoids. Non-limiting examples of essential oils which have highcontent of terpene-ols and esters include bergamot (62% terpenoids);sage (>50% terpenoids); styrax (>50% terpenoids); peppermint (>50%terpenoids); and pine Siberian (75% terpenoids %). Terpenes, aldehydesand ketones vary in their usefulness but as a general group havepotential as insect-repellent.

The foam of the present invention is particularly suitable for theeffective uniform spreading of an insect repellent agent onto largeareas of the skin of humans and animals. The hydrophobic solvent presentin the foam composition helps retain the insect repellent on the skinsurface for an extended period of time.

Yet, in a further embodiment, the foam is suitable for delivery ofinsect-killing agents (insecticides) to an afflicted external surfacearea of humans and animals. Thus, the pharmaceutical or cosmeticcomposition may comprise an insecticide, known in the art ofparasitology. By way of example, such insecticide can be selected fromthe group of permethrin, hexachlorobenzene, carbamate, naturallyoccurring pyrethroids, permethrin, allethrin, malathion, piperonylbutoxide and any combination thereof at a therapeutically effectiveconcentration. Its application is very convenient and it spreads easily,even over hairy areas. The hydrophobic solvent present in the foamcomposition helps retain the insecticide on the treated area for anextended period of time. Furthermore, the presence of a hydrophobicsolvent in the foam eases mechanical removal of lice and nits with acomb.

Anti Cancer Drugs

Anti cancer drugs can also be used according to the present invention asthe drug of choice from skin malignant tumors, such as basal cellcarcinoma, squamous sell carcinoma, melanoma and Kaposi's sarcoma, aswell as the pre-cancerous condition actinic keratosis. In certain cases,topical cytotoxic and antiproliferative drugs are used to treat orprevent such cancers, including 5-fluorouracil, also called 5-FU. 5-FU,as well as any other anti-cancer agents, know in the art of cancermedicine, can be incorporated in the foam at therapeutically effectivelevels.

A preferred family of anticancer drugs, suitable for usage in the foamof the present formulation comprises antiestrogens, such as tamoxifen.Tamoxifen blocks the effects of the hormone estrogen in the body. It isused to prevent or delay the return of breast cancer or to control itsspread.

Photodynamic Therapy Agents

The foam composition of the present invention is also useful to deliverphoto-sensitizing agents, known in the art of photodynamic therapy. Byway of example, such photosensitizers can be selected from the groupcomprising modified porphyrins, chlorins, bacteriochlorins,phthalocyanines, naphthalocyanines, pheophorbides, purpurins, m-THPC,mono-L-aspartyl chlorin e6, bacteriochlorins, phthalocyanines,benzoporphyrin derivatives, as well as photosensitiser precursors, suchas aminolevulinic acid (ALA).

Active Agents for Burns, Wounds, Cuts and Ulcers

The treatment of burns, wounds, cuts and ulcers, using the compositionof the present invention is particularly advantageous. The foam caninclude both anti-infective agents (against bacteria, fungi and/orviruses), antiinflammatory agents (steroidal and/or NSAIDs) and painrelieving components. Upon application, the foam spreads easily,covering the surface of the affected area, and without causing pain.

Skin Care Active Agents

The foam of the present invention is useful and advantageous for skincare and cosmetic care. The combination of oil and water, havingmoisture-retaining properties, in a spreadable foam form, can be used tosubstitute currently used cosmetic skin care creams, lotions, gels, etc.The cosmetic foam compositions of the present invention are suitable forthe further application as “cosmeceutical” preparation (cosmeticproducts with therapeutic benefit), to treat “cosmetic” skin disorders,such as aging skin, wrinkles, hyperpigmentation (melasma, chloasma,freckles, etc.), scaly skin and other skin undesirable properties.

The CTFA Cosmetic Ingredient Handbook describes a wide variety ofnonlimiting cosmetic and pharmaceutical ingredients commonly used in theskin care industry, which are suitable for use in the compositions ofthe present invention. Examples of these ingredient classes include:abrasives, absorbents, aesthetic components such as fragrances,pigments, colorings/colorants, essential oils, astringents, etc. (e.g.,clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate,witch hazel distillate), anti-acne agents, antimicrobial agents (e.g.,iodopropyl butylcarbamate), antioxidants, binders, biological additives,buffering agents, bulking agents, chelating agents, chemical additives,colorants, cosmetic astringents, cosmetic biocides, denaturants, drugastringents, external analgesics, film formers or materials, e.g.,polymers, for aiding the film-forming properties and substantivity ofthe composition (e.g., copolymer of eicosene and vinyl pyrrolidone),opacifying agents, pH adjusters, propellants, reducing agents,sequestrants, skin bleaching and lightening agents (e.g., hydroquinone,kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbylglucosamine), skin-conditioning agents (e.g., humectants, includingmiscellaneous and occlusive), skin soothing and/or healing agents (e.g.,panthenol and derivatives (e.g., ethyl panthenol), aloe vera,pantothenic acid and its derivatives, allantoin, bisabolol, anddipotassium glycyrrhizinate), skin treating agents, thickeners, andvitamins and derivatives thereof.

In any embodiment of the present invention, however, the active agentsuseful herein can be categorized by the benefit they provide or by theirpostulated mode of action. It is to be understood that the active agentsuseful herein can in some instances provide more than one benefit oroperate via more than one mode of action. Therefore, classificationsherein are made for the sake of convenience and are not intended tolimit the active to that particular application or applications listed.

Anti-Acne Active Agents

The compositions of the present invention may contain a safe andeffective amount of one or more pharmaceutically or cosmeticallyacceptable anti-acne active agents. Examples of useful anti-acne activesinclude resorcinol, sulfur, salicylic acid and salicylates,alpha-hydroxy acids, nonsteroidal anti-inflammatory agents, benzoylperoxide, retinoic acid, isoretinoic acid and other retinoid compounds,adapalene, tazarotene, azelaic acid and azelaic acid derivatives,antibiotic agents, such as erythromycin and clyndamycin, zinc salts andcomplexes, and combinations thereof, in a therapeutically effectiveconcentration.

Anti-Wrinkle Active Agents/Anti-Atrophy Active Agents and Agents toTreat Dry and Scaly Skin (Xerosis and Ichthyosis)

The compositions of the present invention may further contain a safe andeffective amount of one or more anti-wrinkle actives or anti-atrophyactives, which can be easily delivered by spreading a foam onto theskin. Exemplary anti-wrinkle/anti-atrophy active agents suitable for usein the compositions of the present invention include sulfur-containing Dand L amino acids and their derivatives and salts, particularly theN-acetyl derivatives; thiols; hydroxy acids (e.g., alpha-hydroxy acidssuch as lactic acid and glycolic acid and their derivatives and salts;or beta-hydroxy acids such as salicylic acid and salicylic acid saltsand derivatives), urea, hyaluronic acid, phytic acid, lipoic acid;lysophosphatidic acid, skin peel agents (e.g., phenol, resorcinol andthe like), vitamin B3 compounds (e.g., niacinamide, nicotinic acid andnicotinic acid salts and esters, including non-vasodilating esters ofnicotinic acid (such as tocopheryl nicotinate), nicotinyl amino acids,nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide andniacinamide N-oxide), vitamin B5 and retinoids (e.g., retinol, retinal,retinoic acid, retinyl acetate, retinyl palmitate, retinyl ascorbate).In the case of dry, scaly skin (xerosis) and ichthyosis such agents canalleviate the symptoms by temporary relief of itching associated withthese conditions.

Anti-Oxidants/Radical Scavengers

A safe and effective amount of an anti-oxidant/radical scavenger may beadded to the compositions of the subject invention, preferably fromabout 0.1% to about 10% (w/w), more preferably from about 1% to about 5%(w/w), of the composition.

Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) andits salts, ascorbyl esters of fatty acids, ascorbic acid derivatives(e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbylsorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherolacetate, other esters of tocopherol, butylated hydroxy benzoic acids andtheir salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid(commercially available under the tradename Trolox.sup.R), gallic acidand its alkyl esters, especially propyl gallate, uric acid and its saltsand alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts maybe used.

The foam of the present invention is suitable for delivering skinprotecting and revitalizing anti-oxidants/radical scavengers. It isfurther pointed out that polyunsaturated fatty acids, containing omega-3and omega-6 fatty acids (e.g., linoleic and linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) are beneficial in the treatment of psoriasisand other skin inflammation conditions. Likewise, emollients andsilicone oils exert moisture-retaining and skin protective effects onthe skin. Thus in a preferred embodiment, a skin protective foam isprovided, wherein the hydrophobic solvent comprises in full or in part,a solvent, selected from the group of emollients, silicone oil and oils,rich in unsaturated fatty acids, thus, affording a synergistictherapeutic effect of the anti-oxidants/radical scavenger agent and thevehicle components.

Self-Tanning Active Agents

The foam of the present invention is particularly suitable for theuniform delivery of a tanning active agent onto large areas of the skin.It is preferable that the compositions contain from about 0.1% to about20%, more preferably from about 2% to about 7%, and still morepreferably from about 3% to about 6%, of the composition, ofdihydroxyacetone, or any other compound, know in the art as anartificial tanning active agent.

Skin Lightening and Whitening Agents

The foam of the present invention is particularly suitable for theuniform delivery of a skin lightening agent. When used, the compositionspreferably contain from about 0.1% to about 10%, more preferably fromabout 0.2% to about 5%, of the composition, of a skin-lightening agent.Suitable skin lightening or whitening agents include those known in theart, including hydroquinone, azelaic acid and other related dicarboxylicacids, and salts and derivatives thereof, retinoids, kojic acid,arbutin, nicotinic acid and its precursors, salts and derivatives,arbutin, ascorbic acid and salts and derivatives thereof (e.g.,magnesium ascorbyl phosphate or sodium ascorbyl phosphate), and herbalextracts (e.g., licorice extract, mulberry extract, placental extract).

In one or more embodiments of the present invention, the foamcomposition comprises a combination of a skin whitening agent and asunscreen agent.

In one or more embodiments of the present invention, the foamcomposition comprises a combination of a skin whitening agent and aninorganic sunscreen agent. When inorganic sunscreen agents, e.g. TiO₂,are rubbed onto the skin, they leave a white coating, which provides animmediate (although transient) whitening effect, which is highlydesirable by the consumer, who wishes to see instant change in his/herappearance. The whitening agent, in combination with the inorganicsunscreen agent in the foam carrier can be easily and uniformlydistributed on the skin surface, thereby affording an even instantwhitening effect, unlike creams that are difficult to spread evenly onskin areas.

Sunscreens

Exposure to ultraviolet light can result in excessive scaling andtexture changes of the stratum corneum. The foam of the presentinvention is advantageous for the delivery of sunscreen agents. Itsapplication is very convenient and it spreads easily over large skinareas. The presence of a hydrophobic solvent in the foam ensures longlasting effect, even while bathing.

As used herein, “sunscreen active” or “sunscreen agent” includes bothsunscreen agents and physical sunblocks. Suitable sunscreen actives maybe organic or inorganic.

Inorganic sunscreens useful herein include the following metallicoxides; titanium dioxide having an average primary particle size of fromabout 15 nm to about 100 nm, zinc oxide having an average primaryparticle size of from about 15 nm to about 150 nm, zirconium oxidehaving an average primary particle size of from about 15 nm to about 150nm, iron oxide having an average primary particle size of from about 15nm to about 500 nm, and mixtures thereof. When used herein, theinorganic sunscreens are present in the amount of from about 0.1% toabout 20%, preferably from about 0.5% to about 10%, more preferably fromabout 1% to about 5%, of the composition.

A wide variety of conventional organic sunscreen actives are suitablefor use herein. Specific suitable sunscreen actives include, forexample: p-aminobenzoic acid, its salts and its derivatives (ethyl,isobutyl, glyceryl esters; p-dimethylaminobenzoic acid); anthranilates(i.e., o-amino-benzoates; methyl, menthyl, phenyl, benzyl, phenylethyl,linalyl, terpinyl, and cyclohexenyl esters); salicylates (amyl, phenyl,octyl, benzyl, menthyl, glyceryl, and di-pro-pyleneglycol esters);cinnamic acid derivatives (menthyl and benzyl esters, a-phenylcinnamonitrile; butyl cinnamoyl pyruvate); dihydroxycinnamic acidderivatives (umbelliferone, methylumbelliferone,methylaceto-umbelliferone); trihydroxy-cinnamic acid derivatives(esculetin, methylesculetin, daphnetin, and the glucosides, esculin anddaphnin); hydrocarbons (diphenylbutadiene, stilbene); dibenzalacetoneand benzalacetophenone; naphtholsulfonates (sodium salts of2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);di-hydroxynaphthoic acid and its salts; o- andp-hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy,7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenylbenzoxazole, methyl naphthoxazole, various aryl benzothiazoles); quininesalts (bisulfate, sulfate, chloride, oleate, and tannate); quinolinederivatives (8-hydroxyquinoline salts, 2-phenylquinoline); hydroxy- ormethoxy-substituted benzophenones; uric and violuric acids; tannic acidand its derivatives (e.g., hexaethylether); (butyl carbotol) (6-propylpiperonyl)ether; hydroquinone; benzophenones (oxybenzene, sulisobenzone,dioxybenzone, benzoresorcinol, 2,2′,4,4′-tetrahydroxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone, octabenzone;4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane; etocrylene;octocrylene; [3-(4′-methylbenzylidene bornan-2-one), terephthalylidenedicamphor sulfonic acid and 4-isopropyl-di-benzoylmethane.

A safe and effective amount of the organic sunscreen active is used,typically from about 1% to about 20%, more typically from about 2% toabout 10% of the composition. Exact amounts will vary depending upon thesunscreen or sunscreens chosen and the desired Sun Protection Factor(SPF).

Agents for Hair Growth Disorders

Agents, which affect the pattern of hair growth, can be suitablyincorporated in the foam of the present invention. Male pattern baldness(MPB), the commonest cause of balding, is induced by the activity of themale hormone dihydrotestosterone (DHT), which converted from the hormonetestosterone by the enzymes 5 alpha reductase. Current treatments of MPBinclude minoxidil and agents, which inhibit 5 alpha reductase, such asfinasteride, spironolactone, azelaic acid and azelaic acid derivativesand salts. Such agents, as well as other agents known in the art, can beincorporated in the foam of the present invention.

It is further pointed out that polyunsaturated fatty acids, i.e., suchwhich include any of the essential fatty acids (EFA's): linoleic andlinolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA)and docosahexaenoic acid (DHA), are also known to contribute to hairgrowth. Thus in a preferred embodiment, a hair growth foam is provided,wherein the hydrophobic solvent comprises in full or in part, an oil,rich in such unsaturated fatty acids.

Figure-Forming Agents; Agents to Treat Cellulite/Slimming

Figure forming agents such as used in the treatment of cellulite and inslimming products, can be suitably incorporated in the foam of thepresent invention. A non-limiting exemplary list of active agents, knownin the treatment of cellulite and in the induction of a slimming effectinclude herbal extracts, such as baldderwack extract, butcher's, broom,cayenne, dandelion, red clover, ginkgo biloba, horse chestnut, witchhazel and borage oil, omega 3 and omega 6 oils, caffeic acid and saltsand derivatives thereof, xanthine agents, such as caffeine, theophilineand pentoxyphilline, and nicotinic acid and salts and derivativesthereof.

Agents to Treat Sunburn, Heat Burn, Radiation Burn, Rash and Itch

Cosmetic and pharmaceutical ingredients which are known in the art ofpharmacology and cosmetology to treat dermatitis, minor skinirritations, sunburn, heat burn, radiation burn, and inhibitinflammation can be beneficially incorporated in the foam of the presentinvention.

Examples of such active agents include chamomile extract (matricariarecutitia), cucumber distillate (cucumis sativus), lavender water(lavendula angustifolia), rose water (rosa damascena), witch hazel(hamamelis virginiana), allantoin, bisabolol, rosehip oil, calendulaoil, azulaene, menthol and camphor.

Use of the Foam as a Lubricating and Protective Foam

There are several potential uses of the foam, particularly thesilicone-oil based foam, as a lubricating foam. Typical examples areshaving foam, moisture protection foam and antifriction foam. For suchpurposes, the foam can be used in its basic composition (withoutadditional formulation aids and active ingredients), or with theaddition of such additives.

Foam for Neutralization and/or Decontamination of Hazardous Chemicalsand Treatment of Heat Burns

It has been reported that povidone iodine antiseptic, a popular iodineproduct, can ameliorate damage to guinea pig skin exposed to mustard gasand other chemical irritants and further reduces, and many timesprevents, damage to human skin after accidental heat burns caused by hotwater, oil or hot steam.

Other active compound, having decontamination abilities, comprise strongoxidants and free radical liberating compounds, such as hydrogen oxide,bleaching agents (e.g., sodium, calcium or magnesium hypochloride andthe like) iodine, chlorohexidine and benzoyl peroxide.

The alcohol-free foam of the present invention, comprising one or moreof the above decontaminating and neutralizing agents can be applied ontothe contaminated skin to form a preventive layer, prior to contaminationmeasure or as a decontamination/neutralization means, right aftercontamination has occurred.

Penetration Enhancers

A penetration enhancer or permeation enhancer is an agent used toincrease the permeability of the skin to a pharmacologically activeagent to increase the rate at which the drug diffuses through the skinand enters the tissues and bloodstream. A chemical skin penetrationenhancer increases skin permeability by reversibly altering thephysiochemical nature of the stratum corneum to reduce its diffusionalresistance. In a review of the technical and patent literature up to1996, numerous chemical compounds were cited as skin penetrationenhancers. Most of the compounds are generally recognized as safe (GRAS)ingredients that would often be considered inert by a formulator(Osborne D W, Henke J J, Pharmaceutical Technology, November 1997, pp58-86.)

Examples of penetration enhancers, according to the present inventioninclude: polyols, such as propylene glycol, hexylene glycol, diethyleneglycol, propylene glycol n-alkanols, terpenes, di-terpenes,tri-terpenes, terpen-ols, limonene, terpene-ol, l-menthol, dioxolane,ethylene glycol, other glycols, and glycerol; sulfoxides, such asdimethylsulfoxide (DMSO), dimethylformamide, methyl dodecyl sulfoxide,dimethylacetamide; monooleate of ethoxylated glycerides (with 8 to 10ethylene oxide units); Azone (1-dodecylazacycloheptan-2-one),2-(n-nonyl)-1,3-dioxolane; esters, such as isopropylmyristate/palmitate, ethyl acetate, butyl acetate, methyl proprionate,capric/caprylic triglycerides, octylmyristate, dodecyl-myristate;myristyl alcohol, lauryl alcohol, lauric acid, lauryl lactate ketones;amides, such as acetamide oleates such as triolein; various surfactants,such as sodium lauryl sulfate; various alkanoic acids such as caprylicacid; lactam compounds, such as azone; alkanols, such as oleyl alcohol;dialkylamino acetates, and admixtures thereof.

Lower alcohols, such as ethanol, propanol, isopropanol, butanol,iso-butanol, t-butanol and pentanol are not considered appropriatepenentartion enhancers according to the present invention, due to theirskin drying and irritation properties.

Yet, another preferred class of penetration enhancers in thecyclodextrines and related compounds. Cyclodextrins are structurallyrelated cyclic oligomaltoses which form a new group of pharmaceuticalexcipients. These are torus-shaped molecules with a hydrophilic outersurface and a lipophilic central cavity. Cyclodextrins are capable offorming water-soluble inclusion complexes with a wide variety oflipophilic water-insoluble drugs by taking up a whole drug molecule, orsome part of it, into the cavity. The cyclodextrin molecules arerelatively large (molecular weight ranging from almost 1000 to over1500), with a hydrated outer surface, and under normal conditions,cyclodextrin molecules will only permeate the skin barrier withconsiderable difficulty. It is generally believed that the cyclodextrinmolecules act as tnue carriers by keeping lipophilic drug molecules insolution and deliver them to the skin surface where they partition fromthe cyclodextrin cavity into the skin.

Further Technical Parameters

The composition of the present invention may be contained in anddispensed from a container capable of withstanding the pressure of thepropellant gas and having an appropriate valve/nozzle for dispensing thecomposition as foam under pressure. A customary liquefied or compressedgas propellant can be added, in the amount of about 5-25% of the totalcomposition. Liquefied propellants are gases that exist as liquids underpressure, including high purity hydrocarbons such as propane, isobutaneand n-butane, dimethyl ether and chlorofluorocarbons (CFCs). Compressedgasses are exemplified by air, nitrogen and carbon dioxide.

A specific embodiment according to the present invention comprisesplacing the composition of the present invention on a patch, occlusivetape or the skin-contact compartment of a transdermal delivery apparatusand applying such object onto the skin, in order to attain effectivesuperficial treatment or enhanced penetration of the drug into the skinor through the skin.

Utilizing such strategy, one can apply drugs, which are currentlyadministered systemically or that require transdermal delivery, in thepreferred therapeutic system of the present invention. Examples for suchdrugs are nicotine, testosterone and other male hormones and malehormone precursors, estrogen and other female hormones and hormoneprecursors, growth hormone, insulin, caffeine, steroidal andnon-steroidal antiinflammatory agents and thyroid hormone substitutes.

The general process, as typically exemplified in Example 1 may beapplied in order to produce the composition of the present invention.

The pharmaceutical carrier according to the present invention can alsobe used to prepare cosmetics for beauty purpose by adding into skin careagents and perfume.

EXAMPLES

The invention is described with reference to the following examples.This invention is not limited to these examples and experiments. Manyvariations will suggest themselves and are within the full intendedscope of the appended claims.

Example 1 General Procedure for Preparing Foamable Composition

Aqueous Phase: Water gelling agent and surface-active agent aredissolved in water, with agitation. The solution is warmed to 50-70° C.Water soluble cosmetic or pharmaceutical active ingredients and optionalwater soluble ingredients are added with agitation to the Aqueous Phasemixture.

Hydrophobic Phase: The hydrophobic solvent is heated to sametemperature. Foam adjuvant agent is added to preheated hydrophobicsolvent. Oil soluble cosmetic or pharmaceutical active ingredients* andoptional oil soluble formulation ingredients are added with agitation tothe Hydrophobic Phase mixture.

The warm Hydrophobic Phase is gradually poured into the warm AqueousPhase, with agitation, followed by Ultraturax homogenization. Themixture is allowed to cool down to ambient temperature. In case of heatsensitive active ingredients, the active ingredient is added withagitation to the mixture after cooling to ambient temperature. Themixture, at ambient temperature, is added to an aerosol container, thecontainer is sealed and appropriate amount of propellant (5-25 w % ofthe composition mass) is added under pressure into the container.

Example 2 Vegetable Oil-Based Foam Carrier Composition

Version Version Version No. 1 No. 2 No. 3 Ingredient % (W/W) Hydrophobicsolvent Soybean oil 40 30.5 20 Water Water 48.5 32.5 61 Foam adjuvantagent Stearyl Alcohol 0.8 1.05 0.73 Surface-active agent Sucrose esterSP70 0.64 0.45 0.8 Water gelling agent Xanthan Gum 0.16 0.11 0.1Methocel ELV15 0.32 0.22 0.28 Other Ingredients Antioxidant 0.02 0.020.02 Preservatives 0.3 0.3 0.3 Fragrance 0.2 0.2 0.2 Foam Specificgravity 0.10 0.15 0.065 (gr/mL)

The compositions use a non-ionic surfactant and contain a combinedamount of surface-active agent, foam adjuvant and water gelling agentranging from 1.83% to 1.92% (w/w). The foam of this example is useful asa carrier of active pharmaceutical and/or cosmetic active ingredients,as exemplified below. It also can be used as a protective product.Additionally, it is also useful as lubricating foam, for variouspurposes.

Example 3 Silicone Oil-Based Foam Carrier Composition

Version Version No. 1 No. 2 Specific Ingredient % (W/W) Hydrophobicsolvent Dimeticone 350* 25 10 Water Water 72 87 Foam adjuvant agentStearyl Alcohol 0.2 0.2 Surface-active agent Sucrose ester SP70 0.8 —Myrj 49P — 0.8 Water gelling agent Xanthan Gum 0.2 0.2 Methocel ELV150.4 0.4 Other Ingredients Antioxidant 0.02 0.02 Preservatives 1 1Fragrance 0.2 0.2 Foam Specific gravity 0.10 ND (gr/mL)*Dimethylpolysiloxane of 350 cps viscosity.

The compositions use only non-ionic surfactant and contain a combinedamount of surface-active agent, foam adjuvant and water gelling agent of1.6% (w/w). The foam of this example is useful as a carrier of activepharmaceutical and/or cosmetic active ingredients, as exemplified below.It also can be used as a protective product. Additionally, it is alsouseful as lubricating foam, for various purposes.

Example 6 Mineral Oil-Based Foam Carrier Composition

Version Version Version Version Version No. 1 No. 2 No. 3 No. 4 No. 5Ingredient % (W/W) Hydrophobic Mineral oil 69 50 50 25 25 solvent WaterWater 28.4 46.7 46.7 71.88 71.9 Foam adjuvant Stearyl Alcohol 0.7 1 10.5 0.5 agent Surface-active Sucrose ester SP70 0.4 0.64 0 0.8 0 agentPEG S-40 0 0 0.64 0 0 Polysorbate-60 0 0 0 0 0.8 Water gelling XanthanGum 0.1 0 0.14 0.2 0.2 agent Methocel ELV15 0.2 0.4 0.32 0.4 0.4 OtherAntioxidant 0.02 0.02 0.02 0.02 0.02 Ingredients Preservatives 1 1 1 1 1Fragrance 0.2 0.2 0.2 0.2 0.2 Foam Specific ND ND ND ND 0.1 gravity(gr/mL)

The compositions use only non-ionic solvents, and the total amount ofsurface active agent, foam adjuvants and water gelling agents rangesfrom 1.4 to 2.1% (w/w). The foam of this example is useful as a carrierof active pharmaceutical and/or cosmetic active ingredients, asexemplified in examples below. It is also useful as lubricating foam,for various purposes.

Example 7 Mixed Oils Foam Carrier Composition

Version Version No. 1 No. 2 Ingredient 25% Oil 12.5% Oil Hydrophobicsolvent Mineral oil 11.2%  5.6% Isopropyl myristate 5.0% 2.5% MCT oil7.5% 3.8% Foam adjuvant agent Stearyl Alcohol 0.5% 0.25%  Water Water73.0%  85.2%  Surface-active agent Sucrose ester SP70 0.8% 0.8%Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.1% 0.1% Watergelling agent Xanthan Gum 0.3% 0.3% Methocel ELV15 0.6% 0.6%

The foams of this example have a non-ionic surfactant to ionicsurfactant ratio (w/w) of 20:1 and 14:1 for versions 1 and 2,respectively. Total amounts of surface active agent foam adjuvant andwater gelling agent is in the range of 1.75-3.5% (w/w). It is useful asa carrier of active pharmaceutical and/or cosmetic active ingredients,as exemplified in examples below. It is also useful as lubricating foam,for various purposes.

The following examples, representing optional drug-containing foams, areprototype formulations, which have not been optimized for stability andinter-component compatibility. Such optimization is a customary need,which can be done, using means, known to those skilled in the art ofpharmaceutical formulation

Example 8 Antibacterial Foam Composition

Version 2 Version 3 Version 4 Version 5 Version 1 “Triple “Fucidic“Metro- “Triple Ingredient “Mupirocin” Antibiotic” Acid” nidazole”Antibiotic” Carrier Ingredients Mineral oil 48.8%  11.2%  48.8%  5.6%5.6% Isopropyl myristate 5.0% 2.5% 2.5% MCT oil 7.5% 3.8% 3.8% StearylAlcohol 0.8% 0.5% 0.8% 0.25%  0.25%  Water  50% 73.0%   50% 85.2% 85.2%  Sucrose ester SP70 0.8% 0.8% — 0.8% Myrj 40 — 0.8% — — Distilled1.2% 0.6% 0.6% monoglyceride Tween 60 0.8% Sodium lauryl 0.05%  0.1%0.1% sulphate Xanthan Gum 0.2% 0.3% 0.2% 0.3% 0.3% Methocel ELV15 0.2%0.6% 0.2% 0.6% 0.6% Active Ingredients Mupirocin   2% Polymyxin BSulfate 10,000 10,000 Units/gr Units/gr Bacitracin Zinc 500 500 Units/grUnits/gr Neomycin Sulfate* 0.05%  0.05%  Pramoxine HCl   1%   1% Fucidicacid   2% Metronidazole   1%

The foams of this example contain 100% non-ionic surfactant or have anon-ionic surfactant to ionic surfactant ratio ranging from 20:1 to 8:1.Total amounts of surface active agent, foam adjuvant and water gellingagent ranges from 2.05-3.5% (w/w). It is useful for the treatment ofbacterial skin infection (general), cellulites, open wounds, cutaneousabscesses, furuncles, insect bite, impetigo, acne, acne-rosacea, andtrichomonas vaginitis.

In certain embodiments, the foam of this example is useful for theprevention, decontamination and/or neutralization hazardous bacterialinfestation (such as warfare organisms).

Example 9 Antifungal Foam Composition

Version 1 Version 2 Version 3 Version 4 Ingredient “Terbinafine”“Clotrimazole” “Nystatin” “Nystatin” Carrier Ingredients Mineral oil48.8%  11.2%  48.8%  5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5%3.8% Stearyl Alcohol 0.8% 0.5% 0.8% 0.25%  Water  50% 73.0%   50% 85.2% Sucrose ester SP70 0.8% 0.8% — 0.8% Myrj 40 — 0.8% — Tween 80 0.8%Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.05%  0.1%0.1% Xanthan Gum 0.2% 0.3% 0.2% 0.3% Methocel ELV15 0.2% 0.6% 0.2% 0.6%Active Ingredients Terbinafine   1% clotrimazole   2% Nystatin 100,000100,000 Units/gr Units/gr

The foams of this example have 100% non-ionic surfactant or have anon-ionic surfactant to ionic surfactant ratio ranging from 20:1 to 8:1.Total surface active agent, foaming adjuvant and water gelling agentranges from 2.05 to 3.5% (w/w). It is useful in the treatment ofdermatophyte infections, Tinea corporis, Tinea pedis, Tinea rubrum,Tinea unguium, Tinea cruris, Tinea barbae, and yeast infections, such asCandidiasis, Tinea versicolor and Candidal vaginitis.

Example 10 Corticosteroid Foam Composition

Version 1 Version 2 Version 3 “Hydro- “Beta- “Dexa- Ingredientcortisone” methasone” methasone” Carrier Ingredients Mineral oil 48.8% 11.2%  5.6% Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% StearylAlcohol 0.8% 0.5% 0.25%  Water  50% 73.0%  85.2%  Sucrose ester SP700.8% 0.4% 0.8% Tween 80 0.4% Distilled 1.2% 0.6% monoglyceride Sodiumlauryl 0.05%  0.1% sulphate Xanthan Gum 0.2% 0.3% 0.3% Methocel ELV150.2% 0.6% 0.6% Active Ingredients Hydrocortisone   1% Betamethasone0.05%  dipropionate Dexamethasone 0.1% acetate Version 4 Version 5Ingredient “Triamcinolone” “Flumetasone” Carrier Ingredients Mineral oil48.8%  48.8%  Stearyl Alcohol 0.8% 0.8% Water  50%  50% Sucrose esterSP70 0.8% 0.8% Sodium lauryl 0.05%  0.05%  sulphate Xanthan Gum 0.2%0.2% Methocel ELV15 0.2% 0.2% Active Ingredients Triamcinolone 0.1%acetonide Flumetasone 0.02%  pivalate

The foams of this example have either 100% non-ionic surfactant or havea non-ionic surfactant to ionic surfactant ratio ranging from 20:1 to16:1. Total surface active agent, foaming adjuvant and water gellingagent ranges from 2.05 to 3.5% (w/w). Indications include psoriasis,contact dermatitis, atopic dermatitis, seborrheic dermatitis, nummulardermatitis, inflammatory acne, chronic dermatitis of the hands and feet,generalized exfoliative dermatitis, stasis dermatitis, lichen simplexchronicus, herpes gestationis and pruritic urticarial papules andplaques of pregnancy.

Example 11 Antiviral Foam Composition

Version 1 Version 2 Version 3 Ingredient “Acyclovir” “Acyclovir”“α-Interferon” Carrier Ingredients Mineral oil 48.8%  11.2%  5.6%Isopropyl myristate 5.0% 2.5% MCT oil 7.5% 3.8% Stearyl Alcohol 0.8%0.5% 0.25%  Water  50% 73.0%  85.2%  Sucrose ester SP70 0.8% 0.8% Tween80 0.8% Distilled monoglyceride 1.2% 0.6% Sodium lauryl sulphate 0.1%Xanthan Gum 0.2% 0.3% 0.3% Methocel ELV15 0.2% 0.6% 0.6% ActiveIngredients Acyclovir   5%   5% α-Interferon 105 IU/g

The foams of this example have either 100% non-ionic surfactant or havea non-ionic surfactant to ionic surfactant ratio of 14:1. Total surfaceactive agent, foaming adjuvant and water gelling agent ranges from 2.05to 3.5% (w/w). Indications include Herpes simplex, Herpes zoster, Herpesgestationis and Herpes simplex genital ulcers.

Example 12 Insect Repellent Foam Composition

Ingredient % Isopropyl myristate 2.0% MCT oil 2.0% Stearyl Alcohol 1.2%Water 64.0%  Sucrose ester SP70 0.8% Sodium lauryl sulphate 0.1% XanthanGum 0.3% Methocel ELV15 0.6% Propylene glycol  15% DEET  15%

Example 14 Comparative Tolerability and Acceptability Study of aCorticosteroid Foam Composition Vs. a Conventional Ointment

A panel of eight testers was requested to apply about 0.5 gr. of thefoam preparation of example 10, Version 2 on one arm and 0.5 gr. ofcommercial Betamethasone valerate ointment, in a double blind fashion.They were asked to describe their feeling about the ease of application,ease of spreading, spreadability and penetrability of each of theproducts and to give their general rating for each of the products on ascale of 0-3 (0=poor; 1=barely acceptable; 2=acceptable and3=excellent).

As demonstrated in the following table, the foam preparation of example10, Version 2 obtained higher rates in all aspects of the test.

Commercial Betamethasone Foam Preparation Valerate Ointment PropertyMean Rating Mean Rating Ease of application 2.3 1.6 Ease of spreading2.5 1.9 Spreadability 2.9 1.2 Penetrability 2.0 1.5 Lack of stickyfeeling 2.4 1.0 Lack of greasy feeling 2.2 1.0 Lack of shiny look 1.91.4 Overall rating 2.5 1.4

Example 15 Human Safety and Efficacy Study of a CorticosteroidComposition in Psoriasis Patients

Two patients with mild to moderate psoriasis were administered topicallya Betamethasone 0.12% foam (example 10, Version 2) twice daily for twoweeks. Both patients improved significantly, as manifested by clearanceof the psoriatic plaques flattening of the thickened lesions. FIG. 1provides an exemplary response to treatment in the elbows of one ofthese patients. While betamethasone is know for its effect in psoriasis,such a beneficial effect after 14 days treatment is exceptional. Theaccelerated effect was attributed to the improved convenience andtherefore, improved compliance.

Example 16 Human Safety and Efficacy Study of a CorticosteroidComposition in Psoriasis Patients

Four patients with moderate to severe, disseminated atopic dermatitiswere administered topically a Betamethasone 0.12% foam (example 10,Version 2) twice daily for two weeks. All patients improvedsignificantly, as manifested by complete clearance of all treatedlesions. FIG. 2 provides exemplary responses to treatment in differentbody areas, after 10 days of treatment. While betamethasone is know forits effect in atopic dermatitis, such a beneficial effect after 10 daystreatment is exceptional. The patients claimed that the use of the foamof the present invention was significantly more convenient than thecorresponding cream and ointment. Thus, the accelerated effect wasattributed to the improved convenience and therefore, improvedcompliance.

Example 17 Foam Compositions with Urea

Component % w/w Mineral oil 6.00 6.00 6.00 6.00 Isopropylmeristat 6.006.00 6.00 6.00 Glyceryl monostearate 0.50 0.50 0.50 0.50 Stearyl alcohol0.20 0.20 0.20 1.00 Urea 10.00 10.00 10.00 10.00 Xantan gum 0.30 0.300.30 0.30 Methocel K100M 0.30 0.30 0.30 0.30 Myrj 52 3.00 TWEEN 80 1.00Myrj 49p 3.00 TWEEN 60 1.00 1.00 1.00 Cocamidopropylbetain 0.50 0.50Phenonip 0.30 0.30 0.30 0.30 Water to 100.0 to 100.0 to 100.0 to 100.0Butane/propane 8.00 8.00 18.00 18.00 FoamQuality E E E E Density n/a0.023 n/a 0.024

Example 18 Compositions with Various Penetration Enhancers

Component % w/w Mineral oil 6.00 6.00 6.00 6.00 6.00 Isopropyl myristate6.00 6.00 6.00 6.00 6.00 Glyceryl monostearate 0.50 0.50 0.50 0.50 0.50Stearyl alcohol 1.00 1.00 1.00 1.00 1.00 Xantan gum 0.30 0.30 0.30 0.300.30 Methocel K100M 0.30 0.30 0.30 0.30 0.30 TWEEN 60 1.00 TWEEN 80 1.001.00 1.00 1.00 MYRJ 49p 3.00 3.00 3.00 3.00 3.00 Propylen glycol 5.00Glycofurol 1.00 10.00 Urea 10.00 Cocoamidopropyl- 0.50 0.50 0.50 0.500.50 bethaine Lidocain base 4.00 4.00 4.00 4.00 4.00 Phenonip 0.30 0.300.30 0.30 0.30 Water to 100 to 100 to 100 to 100 to 100 Butane/propane 88 8 16 10 Foam Quality E E E E E Density 0.020 0.018 0.019 0.019 0.018

Component % w/w % w/w Isopropyl myristate 30.00 30.00 Glycerylmonostearate 0.50 0.50 Stearic acid 0.45 0.45 Xantan gum 0.30 0.30Methocel K100M 0.30 0.30 TWEEN 80 1.00 1.00 MYRJ 49p 3.00 3.00Cocoamidopropylbethaine 0.50 0.50 Transcutol p 20.00 20.00 Hydrophilicdrug Effective concentration Hydrophobic drug Effective concentrationPhenonip 0.30 0.30 Water to 100.0 to 100.0 Butane/propane 8.00 8.00FoamQuality E E Density 0.020 0.020

1. An alcohol-free foamable pharmaceutical or cosmetic carrier, comprising: (a) a foamable composition comprising: about 2-75% by weight of composition of a liquid, non-volatile hydrophobic solvent; about 80-98% by weight of composition of water; about 0.1% to 5% by weight of composition of a foam adjuvant agent selected from the group consisting of fatty alcohols, fatty acids, hydroxyl-substituted fatty alcohols, hydroxyl-substituted fatty acids, and fatty acids and fatty alcohols including at least one double bond in its carbon atom chain; about 0.1% to 5% by weight of composition of a surface-active agent; and about 0.1% to 5% by weight of composition of a water gelling agent. and (b) a liquefied or compressed gas propellant in a container, which upon release provides a breakable foam suitable for topical or muscosal administration. 2-87. (canceled) 